Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline ... [more ▼]

Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline, the loss of ability to perform activities of daily living, is related to the decrease in physiological reserves and frailty and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty were explored and 20 immunological parameters were affected in seniors with functional decline. IGF-1, thymopoeisis and telomere length were part of these markers. A strong relationship between insulin-like growth factor-1 (IGF-1) and thymic ouput was evidenced. IGF-1, mediator of GH, was subsequently shown to induce IL-7 secretion in cultured primary human thymic epithelial cells (TECs). We are also exploring the ‘stress hypothesis’ according which an acute stress is the discriminator revealing a frailty susceptility. GH can counteract the deleterious immunosuppressive effect of stress-induced steroids. Under non-stressing conditions, the immunosenescent system preserves physiological responses, while in stressing conditions, the combination of immunosenescence and a defect in somatotrope axis might lead to functional decline. [less ▲]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in ... [more ▼]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. Effect of GH on T-cell differentiation was explored through thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1, displayed distinct expression profiles depending on the developmental stage. The protein concentration of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and GHR antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T-cell differentiation could implicate a different local growth factor or cytokine. [less ▲]

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process ... [more ▼]

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of ‘forbidden’ self-reactive T cells and a deficiency in self-antigen specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in β cells by autoimmunity, a novel type of vaccination is currently developed for prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders. [less ▲]

Background and aims: Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this ... [more ▼]

Background and aims: Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this perspective in acutely ill older patients. This prospective study was designed to determine whether biological markers can improve the predictive value of a clinical screening tool to assess the risk of functional decline in hospitalized older patients. Methods: Patients aged 75 years and over admitted for hip fracture, acute heart failure or infection (n=118) were recruited. The clinical screening tool SHERPA was filled in on admission, with concomitant measurement of interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP), white blood cells, urea, albumin, pre-albumin and total cholesterol. Functional decline was defined as a decrease of one point in the activities of daily living scale between pre-admission and 3-month post-discharge status. We compared the discrimination calibration of SHERPA vs SHERPA+, a logistic regression model including SHERPA and selected biomarkers. Results: Three months after discharge, functional decline had occurred in 46 patients. IL-6 and IGF-1 were selected, since their levels were significantly different between decliners and non-decliners, and were included in the new logistic regression model SHERPA+. Areas under the ROC curve [95% CI] for functional decline prediction were 0.73 [0.63-0.81] for SHERPA vs 0.79 [0.69-0.86] for SHERPA+ (p=0.14). However, SHERPA+ was better calibrated, as the average predicted risk of functional decline within subgroups matched the proportion which actually underwent functional decline (Brier score=0.185). Since functional decline was higher in patients with hip fracture, the SHERPA+ model was challenged by including the diagnosis. Only SHERPA, IGF-1 and diagnosis were significantly associated with functional decline. Conclusions: Selected biological markers may marginally improve the clinical prediction of post-discharge functional decline in hospitalized patients, and may allow to stratify them appropriately. The predictive value of these biomarkers is not fully independent of disease status. Further studies are needed to confirm these results in a cohort representative of older patients admitted through the emergency department. (Aging Clin Exp Res 2011; 23: 106-111) [less ▲]

The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart ... [more ▼]

The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress weremore abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of CD28, CD69, LCK, HMOX1, TNFRSF1A transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of BCL2, CASP8, CCL5, DDIT3, EGR3, IL10RB, IL1R2, SERPINB2 and TIMP1 were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture. [less ▲]

The abundance of a selection of transcript species involved in in!ammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days ... [more ▼]

The abundance of a selection of transcript species involved in in!ammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days 2–4 after hospitalization) or convalescence phase (days 7–10) and 28 healthy aged controls. Twenty-nine differentially abundant transcripts were identi"ed in acute phase versus healthy ageing. Twelve of these transcripts remained differentially abundant in convalescence phase, and 22 were similarly differentially abundant in acute phase of geriatric infectious diseases. Seven of these 22 transcripts were previously identi"ed as differentially abundant in PBMC of healthy aged versus healthy young controls, with further alteration for CD28, CD69, LCK, CTSD, HMOX1, and TNFRSF1A in acute phase after geriatric hip fracture and infectious diseases. The next question is whether these alterations are common to other geriatric diseases and/or preexist before the clinical onset of the diseases. [less ▲]